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Major obesity gene is lost in the shuffle

04/01/2006

Major obesity gene is 'lost in the shuffle'

Researchers report that genome evolution in the lower apes erased a 'fat gene'

TOKYO, Japan, Sat., April 1, 2006 – Scientists from The University of Tokyo announce today that gibbons, arboreal primates that inhabit the jungles of Southeast Asia, do not carry a major obesity gene that is present in the genomes of all other primates, including humans. This omission is due to a genetic mis-shuffling event that occurred approximately 25 million years ago. Their results are reported in the April issue of the scientific journal Genome Research.

Agouti signaling protein (ASIP) was the first "obesity gene" to be cloned and characterized by geneticists, but it also plays an important role in other physiological processes – ranging from hair color determination to energy homeostasis. Mice that over-produce ASIP are extremely obese, exhibit symptoms of diabetes, and have yellow fur, while mice that lack the ASIP gene are black in color. The gene is widely expressed in tissues throughout the body, so it presumably plays a yet-to-be-defined role in additional biological processes.

The ASIP gene has been characterized in fish, chickens, and various mammals, but no detailed investigation of ASIP has yet been performed in primates. With this in mind, Takafumi Ishida, Associate Professor of Biological Sciences at The University of Tokyo, and his colleague Kazuhiro Nakayama set out to compare the DNA sequences of the ASIP gene from various primates, including Old and New World monkeys, gibbons, gorillas, and chimpanzees. They discovered that the ASIP gene was highly conserved among most of these primates, but, surprisingly, a 100-kilobase segment of DNA harboring the ASIP gene was missing in gibbons.

"We found that this deletion occurred between two pieces of DNA that are quite abundant in primate genomes, called Alu elements," explains Nakayama. "We located one copy of a specific Alu element on either side of the ASIP gene. Our study shows that during the evolution of gibbons, these Alu elements lined up and recombined with each other, erasing approximately 100 kilobases of DNA that spanned the ASIP gene."

Ranging in size from 15 to 22 pounds, gibbons possess lithe, slender bodies that enable them to swing agilely across branches and vines in the jungles. Ishida and Nakayama speculate that the loss of the ASIP gene in gibbons may have played a role in the evolution of the gibbons' uniquely slender body shape and size, although there is no biochemical or physiological evidence to suggest this.

"In essence, we are observing the result of an ancient gene 'knockout' experiment," Ishida explains. "The deletion – or 'knockout' – of the ASIP gene may have helped gibbons adapt to arboreal niches. We know that the ASIP protein regulates lipid metabolism in humans, so there is certainly reason to presume that this deletion contributed to the gibbons' remarkably small body mass, enabling them to thrive in the jungle canopy."

Ishida points out that future studies of gibbons and other primates will enable scientists to examine the physiological effects of the ASIP deletion. "This will allow us to identify the specific metabolic roles of ASIP in vivo by comparing a species that has the gene versus a species that lacks the gene," he says.

Takafumi Ishida, principal investigator on this study, has agreed to be contacted by e-mail (tishida@biol.s.u-tokyo.ac.jp) for additional information.

Interested reporters may obtain pre-print copies of the manuscript from Maria Smit, Assistant Editor, Genome Research (smit@cshl.edu) The manuscript will be published in the April issue of Genome Research and will appear online (DOI: 10.1101/gr.4763906) on April 3.

Genome Research ( www.genome.org ) is an international, monthly, peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly cited primary research journals in genetics and genomics.

Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit www.cshlpress.com .

Genome Research issues press releases to highlight significant research studies that are published in the journal.